Abstract
Uric acid is the highly insoluble end-product of purine metabolism in humans. Serum levels exceeding the solubility threshold can trigger formation of urate crystals resulting in gouty arthritis. Uric acid is primarily excreted through the kidneys with 90% reabsorbed back into the bloodstream through the uric acid transporter URAT1. This reabsorption process is essential for the high serum uric acid levels found in humans. We discovered that URAT1 proteins from humans and baboons have higher affinity for uric acid compared with transporters from rats and mice. This difference in transport kinetics of URAT1 orthologs, along with inability of modern apes to oxidize uric acid due to loss of the uricase enzyme, prompted us to ask whether these events occurred concomitantly during primate evolution. Ancestral URAT1 sequences were computationally inferred and ancient transporters were resurrected and assayed, revealing that affinity for uric acid was increased during the evolution of primates. This molecular fine-tuning occurred between the origins of simians and their diversification into New- and Old-World monkey and ape lineages. Remarkably, it was driven in large-part by only a few amino acid replacements within the transporter. This alteration in primate URAT1 coincided with changes in uricase that greatly diminished the enzymatic activity and took place 27–77 Ma. These results suggest that the modifications to URAT1 transporters were potentially adaptive and that maintaining more constant, high levels of serum uric acid may have provided an advantage to our primate ancestors.
Highlights
Serum uric acid in humans is tightly regulated to a normal range of 210–420 mM (3.5–7 mg dlÀ1) (Feig et al 2006)
S1, Supplementary Material online) demonstrates that hURAT1 is a high affinity and low capacity uric acid transporter compared with rURAT1
We have demonstrated using evolutionary inference and quantitative biochemical transport assays that URAT1 acquired both a higher affinity and a lower capacity for the transport of uric acid during primate evolution
Summary
Serum uric acid (sUA) in humans is tightly regulated to a normal range of 210–420 mM (3.5–7 mg dlÀ1) (Feig et al 2006). Applying ancestral sequence reconstruction to resurrect ancient uricases from early primate evolution suggests that the enzyme accumulated a series of amino acid replacements that rendered it inactive and this occurred before the gene itself accumulated substitutions to generate a pseudogene by way of premature stop-codons (Wu et al 1994; Oda et al 2002; Kratzer et al 2014). This lack of activity is likely one reason why sUA levels in hominoids are generally 3–10 times higher than in other mammals. Regardless, the increased sUA may have provided benefits during the course of primate evolution
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